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Original Article

The relationship between deficiency and function in the first trimester of pregnancy

Farahnaz Rostami 1, Lida Moghaddam-Benaem2, Navid Ghasemi 3, Sedighe Hantoushzadeh 4*

1Department of Midwifery & Reproductive Health, Faculty of Medical Sciences, Tarbiat Modares University, Al-e-Ahmad Highway, Tehran, Iran. 2 Department of Reproductive Health & Midwifery, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. 3 Department of medicine, faculty of Medical Sciences Tehran, Islamic Azad University, Tehran, Iran.4 Maternal, fetal & Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

Aims and Objective: There are few studies about the relationship between vitamin D deficiency and thyroid levels in pregnancy. This study aimed to assess the relation serum vitamin D levels with thyroid in the first trimester of pregnancy in Iran. Methods: In this case-control research 430 pregnant women (215 mothers with vitamin D deficiency, and 215 without this deficiency) attending prenatal clinics in Tehran, Iran were studied. 25 hydroxy vitamin D levels and [free tetraiodothyronine (FT4), thyroid stimulating hormone (TSH), and free (FT3)] were measured in all mothers. Data were analyzed using SPSS version 22 software. Kolmogorov-Smirnov test was used for normality testing of continuous variables; Student T-Test, and Mann-Whitney U test were used to compare the continuous parametric and nonparametric variables respectively in the 2 study groups; Linear regression model was used to assess the effect of potentially effective variables besides vitamin D on thyroid function tests. Results: In Mann-Whitney U test performed, T4 levels (mean± SD) were significantly higher in vitamin D deficiency group compared with the control group (20.8 ±32.5 vs.14.4 ± 24.1 ng/dl, P-value: 0.04), but there were no significant differences between the 2 study groups regarding TSH, and free T3 levels. In Linear regression analysis, assessing the effects of vitamin D deficiency plus maternal age, Body Mass Index, and number of pregnancies on thyroid function tests, it was shown that vitamin D deficiency had only a significant direct relation with free T4 levels (β: 0.122, P-value: 0.01), but had no significant relations with the other thyroid function tests namely TSH, and free T3. Conclusion: A significant direct relationships were observed between Vitamin D deficiency with the level of thyroxin (T4) during early pregnancy. higher levels of T4 in vitamin D deficient mothers. Due to the negative effects of Vitamin D deficiency and on the mother and fetus, further studies should be conducted which may help in more accurately screening during pregnancy.

Keywords: Vitamin D, Vitamin D deficiency, Thyroid function, Pregnancy.

important point here is that both vitamin D and thyroid INTRODUCTION hormones, attach to similar receptors called hormone receptors. On the other hand, a kind of gene in the Vitamin D Vitamin D is a -soluble vitamin and a , has been shown to predispose persons to which its main role is calcium and . The autoimmune . Therefore, any change in deficiency of this vitamin is known as a worldwide problem. vitamin D levels may increase the risk of thyroid Evidence has shown that vitamin D deficiency may increase the risk of a wide range of chronic diseases. Also, its deficiency can increase the likelihood of autoimmune Address for correspondence: Mrs. Sedighe Hantoushzadeh, Maternal, fetal & Neonatal Research Center, Tehran University diseases, upper respiratory tract infection, , of Medical Sciences, Tehran, Iran. [1] cardiovascular disease, and cancer . Email: [email protected]

This vitamin is active in the immune system and its role as a This is an open-access article distributed under the terms of the Creative Commons modulator of the immune system has recently been Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, [2] highlighted Several clinical trials have shown that tweak, and build upon the work noncommercially, as long as the author is credited autoimmune diseases such as lupus erythematosus, [3] and the new creations are licensed under the identical terms. Multiple sclerosis[4], Rheumatoid arthritis, [5] Hashimoto's thyroiditis, and are associated with vitamin How to cite this article: Rostami, F., Moghaddam-Benaem, L., D deficiency. [6] Ghasemi, N., Hantoushzadeh, S. The relationship between Vitamin D deficiency and thyroid function in the first trimester of pregnancy. Arch Pharma Pract 2020;11(S1):132-7. Vitamin D receptors are present in various tissues of the body such as , thyroid gland, and myocardium, etc. [7] The

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Rostami et al.: The relationship between Vitamin D deficiency and thyroid function in the first trimester of pregnancy

abnormalities. For these reasons, it is important in patients This case-control study was conducted on 450 pregnant with thyroid disease to understand the effects of Vitamin D women in their first trimester of pregnancy in a referral on health. [8, 9] The main mechanisms of the role of vitamin D prenatal clinic (which admitted patients from all over the city) in autoimmune diseases have not been fully understood but in Tehran, Iran during September 2017 – 2018. In this clinic in a with a review of vitamin D receptor (VDR) measurements of calcium and vitamin D levels were in patients with thyroiditis, increased thyroid disease risk was performed as part of routine prenatal laboratory tests for all shown.[10] Recent evidence demonstrates the relationship pregnant women in their first trimester of pregnancy. 215 between vitamin D and Hashimoto thyroiditis and Graves ' pregnant women who had vitamin D levels lower than 30 disease. Vitamin D may have a role in thyroid diseases, ng/ml were recruited in the study as the case group, and 215 including thyroiditis and thyroid carcinoma.[11] It was also mothers with normal vitamin D levels (equal to or higher than seen that Vitamin D deficiency, especially the amounts of less 30 ng/ml) were recruited as the control group.[28] than 12.5 ng/ml, was considered as a risk factor for autoimmune disease and thyroid disease.[12] Besides, an Inclusion criteria in the study were: age 18-40 years, increased level of TSH was observed after the administration less than 14 weeks, not have a chronic disease, of vitamin D supplements. [13] Another study reported the and malabsorption, single pregnancy, not taking any effect of pregnancy suppressant on thyroid parameters supplements except multivitamins, and Iranian nationality. (thyroxin (T4) hormone triiodothyronine (T3) and thyroid- stimulating hormone (TSH)).[14] Controls and cases were matched by frequency matching method in terms of age, number of pregnancies, age of Even though many studies have evaluated the role of vitamin marriage and body mass index (BMI). D in thyroid disease, few studies have investigated the effects of 25-hydroxy vitamin D on thyroid hormones in pregnancy Exclusion criteria were, the unwillingness of mothers to and their effects on maternal and fetal health. [15-17] Pregnancy continue participation in the study, mothers who had a may be associated with changes in homeostasis and vegetarian diet or a special diet, mothers who had other physiological changes that eventually lead to altered hypothyroidism before pregnancy and used thyroid function. [18] Maternal thyroid function should be tablets during Pregnancy. maintained normally, especially in the first trimester. In the first trimester, the fetus is fully dependent on maternal thyroid All eligible mothers were enrolled after being given complete hormones for development. [19] Several studies have information about the study, and signing the informed shown that vitamin D deficiency and thyroid function can consent until the sample size was completed. They also lead to a series of adverse complications during pregnancy, completed their sociodemographic and obstetric including gestational hypertension [20, 21] preeclampsia [22, 23] questionnaire. Preterm delivery [21, 24] intellectual and neurological growth disorder in children [17, 25] and so on. Therefore, to maintain a Measurement healthy pregnancy and normal fetal skeletal development and Vitamin D was measured by ELISA method using MAN Co to prevent preeclampsia, an optimal vitamin D level should Kit. Thyroid function tests (T3, T4, TSH) were conducted by [26] be maintained to ensure fetal health. Also hypothyroidism Roche ELISA Modular Analytics Cobas e411 (kit Roche is common in pregnant women, and if screening is performed Diagnostics, Mannheim, Germany) at Nilou Laboratory. only in high-risk groups, 25% of pregnant women with Mothers' weight and height were measured at the first subclinical and hidden hypothyroidism are not explicitly prenatal visit using unique tools for all participants. Body [27] diagnosed. Mass Index (BMI) was calculated by dividing weight (kg) on height2 (m2). Objectives Given the rather high prevalence of vitamin D deficiency and Sample size thyroid disorders in Iran, and their adverse effect on the Convenience sampling was performed and the sample size maternal and fetal outcomes of pregnancy, and also lack of was calculated through the Pokak formula,[29] having sufficient evidence about the relations between vitamin D considered error type 1= 0.05 and, study power 80% for deficiency and thyroid function during pregnancy, this study comparing the mean of the two groups, approximately 195 aimed to investigate the relations between serum levels of individuals with a 10% rate of loss, per group, were 215 vitamin D in pregnant women, and also vitamin D deficiency, persons. Because the researchers found no similar study, a with thyroid function tests [Thyroid-stimulating hormone pilot study was performed on 100 pregnant women (50 with (TSH), thyroxin (FT4)) and triiodothyronine hormone (FT3)] vitamin D deficiency and 50 without deficiency) in the first in the first trimester of pregnancy in a referral prenatal clinic trimester of pregnancy to assess their TSH levels. in Tehran.

2 2 METHODS 푆1 +푆2 2 Study design and participants 푛 = (휇1−휇2) × 푓(훼, 훽)

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S1=1.8 (group 1 TSH standard deviation) S2=1.2 (group 2 The results showed that there was a significant relationship TSH standard deviation) µ1 =2.3 (mean of the TSH first between serum levels of vitamin D and Thyroxin (T4) in early group) µ2 =2.0 (mean of TSH the second group) pregnancy, but there were no such findings about T3, and TSH. The mean level of T4 was higher in mothers with vitamin D deficiency, whereas the mean T3 and TSH levels Ethical 푓(훼, 훽considerations) = 3.8 in this group were lower (insignificantly) and it seems that This study was conducted after obtaining the Code of Ethics vitamin D deficiency in the first trimester of pregnancy may in Tarbiat Modarres Faculty of Medical Sciences (IR. TMU. increase T4 levels. REC 1395.368), Tehran, Iran. The results of the present study were in contrast to the results Statistical analysis of a study in Italy. Their results showed a partial correlation, Data collection and analysis were performed using SPSS but there was a significant relationship between the sufficient software version 22. Kolmogorov-Smirnov test was used for level of 25-hydroxyvitamin D and low TSH level in pregnant normality testing of continuous variables, and Mann- women (sufficient vitamin D levels above 30 ng/ml). The Whitney U test was used to compare the continuous study found that during pregnancy there was no evidence of nonparametric variables in the 2 study groups (all continuous the effect of vitamin D on thyroid hormones such as FT4. variables had non-normal distributions); Liner regression However, the correlation between TSH levels with 25- model was used to assess the effect of potentially effective hydroxyvitamin D may reflect the effect of vitamin D on variables besides vitamin D, on thyroid function tests. P- pituitary TSH production, as has been shown in previous [30] value< 0.05 was considered statistically significant. studies. But the present study showed the effect of vitamin D on Thyroxin (T4). ESULTS: R A Study in Sudan showed that pregnancy in healthy women In this study, 430 pregnant mothers were recruited in the had a suppressive effect on all thyroid parameters (TSH, T4, study as two groups of case (with vitamin D deficiency) and and T3). [14] In the present study, no such effect was found in control (without vitamin D deficiency) (215 in each the group of women with sufficient vitamin D. Another study group). In Mann-Whitney U test performed, there were no was conducted among Korean pregnant women which statistically significant differences between the two groups in showed that there was no significant difference between the term of distribution of the variable: age, number of level of 25-hydroxyvitamin D and autoimmune thyroid pregnancies, age of marriage first trimester BMI and Calcium disease. [31] levels (Table 1). A study showed that there was no relationship between 25- Also in Mann-Whitney U test, there were significant hydroxyvitamin D, FT4, and FT3 during pregnancy, differences in mean serum levels of vitamin D, and T4 in the however, there was a significant correlation in pregnant 2 groups of case and control (P=0.04); and T4 levels higher women with adequate vitamin D levels (more than 30 ng/ml) in cases (20.8 vs. 14.4 ng/dl). But there were no significant between vitamin D and lower TSH. [32] In a study performed differences about T3 (P=0.39), and TSH (P=0.51) in the 2 during pregnancy, no association was found between 25- study groups (table 2). Hydroxy Vitamin D and Thyroid function, despite vitamin D deficiency among these women.[33] Different studies have had Linear regression analysis was performed to assess the impact different results about vitamin D levels and thyroid hormones of vitamin D deficiency, and some potentially effective during pregnancy. Another case-control study among non- factors including maternal age, BMI, and number of pregnant and healthy women showed no significant pregnancies on thyroid function tests (free T3, free T4, and relationship between vitamin D level and hypothyroidism.[34] TSH levels). According to linear regression analysis, there was a significant relationship only between vitamin D In other studies, there was a significant correlation between deficiency and T4 (β: 0.12, P-value: 0.01); T4 level was vitamin D, Hypothyroidism and its prevalence in women. [35, higher in mothers with vitamin D deficiency (Table 3). 36] Furthermore, one other study found there were no significant relationships between vitamin D, Hashimoto’s DISCUSSION Thyroiditis and Hypothyroidism; this study showed that This study aimed to investigate the relations between vitamin serum levels of 25-Hydroxy vitamin D were lower in the D deficiency, and thyroid function tests (free T3, free T4, and Hashimoto’s Thyroiditis and Hypothyroid group compared to TSH) in the first trimester of pregnancy in a referral prenatal the healthy control group. [37] In the other study, it was clinic in Tehran, Iran, during September 2017 – 2018. Normal observed that serum levels of vitamin D were lower in pregnancy increases thyroxine stimulation and leads to patients with Hashimoto's Thyroiditis compared to control. incidence of temporary becomes pregnant in [38] The prevalence of vitamin D and zinc deficiency were the first trimester. significantly higher in patients with hypothyroidism compared to healthy controls. [39] Serum vitamin D levels were significantly lower at the beginning of Graves' disease,

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Rostami et al.: The relationship between Vitamin D deficiency and thyroid function in the first trimester of pregnancy but there was no significant association between vitamin D 5. Yesil H, Sungur U, Akdeniz S, Gurer G, Yalcın B, Dundar U. and thyroid hormones. [40] Studies have shown vitamin D Association between serum vitamin D levels and neuropathic pain in rheumatoid arthritis patients: A cross sectional study. Inter J deficiency as a risk factor for autoimmune thyroiditis and Rheumatic Dis 2018;21:431-439. thyroid function.[41-44] 6. Tamer G, Arik S, Tamer I, Coksert ‐ D. Relative vitamin D insufficiency in Hashimoto's thyroiditis. Thyroid 2011;21:891-6. According to performed studies, researchers have guessed 7. Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med that 25-hydroxy vitamin D and thyroid antibodies act 2010;88:441-50. independently and have similar complications in 8. Friedman TC. Vitamin D deficiency and thyroid disease 2019. pregnancy.[45] This evidence and the investigation 9. Feng M, Li H, Chen S-F, Li W-F, Zhang F-B. Polymorphisms in the emphasized the role of vitamin D in pregnancy and its vitamin D receptor gene and risk of autoimmune thyroid diseases: a meta-analysis. Endocrine 2013 318-26. relationship with thyroid diseases, but the exact mechanism 10. Yazici D, Yavuz D, Tarcin O, Sancak S, Deyneli O, Akalin S. Vitamin has not been investigated yet, and explaining the underlying D receptor gene Apal, Taql, FokI and BsmI polymorphisms in a group mechanism needs further research. of Turkish patients with Hashimoto's thyroiditis. Minerva Endocrinol. 2013;195-201 11. Kim D. The Role of Vitamin D in Thyroid Diseases. Int J Mol Sci Up to now, vitamin D and thyroid function related studies 2017;18:1949. have shown conflicting results. These conflicting results can 12. Vondra K, Stárka L, Hampl R. 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Increased Prevalence of Auto Immunity T However, if according to previous studies, conclude that among Pregnant Women in Kolkata, West Bengal-Is Hypovitaminosis D to Be Blamed For It? Inter J Sci Healthcar Res vitamin D deficiency is a risk factor for hypothyroidism and 20199;4:3. autoimmune thyroiditis, and if those conditions coincided 17. Li Y, Shan Z, Teng W, Yu X, Li Y, Fan C, et al. Abnormalities of together during pregnancy, the imminent harm comes to both maternal thyroid function during pregnancy affect the mother and her fetus may be severe. Therefore, the neuropsychological development of their children at 25–30 months. Clin Endocr 2010;72:825-9. correction of both disorders is recommended to minimize any 18. Medici M, Korevaar TI, Visser WE, Visser TJ, Peeters RP. Thyroid potential risks. The limitations in the present study were the function in pregnancy: what is normal? Clin Chemist 2015;61:704- lack of testing thyroid antibody and 13. testing as well as seasonal variations during study. 19. Van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early CONCLUSION: pregnancy: a systematic review. Hum Reprod Update 2011;17:605- 19. The results of this study showed that Vitamin D deficiency 20. Krassas G, Poppe K, Glinoer D. Thyroid function and human had a significant direct relationship with the level of Thyroxin reproductive health. Endocrinol Rev 2010;31:702-55. (T4) in pregnant women. T4 levels were higher in mothers 21. Baker AM, Haeri S, Camargo CA Jr, Espinola JA, Stuebe AM. A with vitamin D deficiency in the first trimester of pregnancy. nested case-control study of midgestation vitamin D deficiency and risk of severe preeclampsia. 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29. Alonzo TA, Pepe MS, Moskowitz CS. Sample size calculations for comparative studies of medical tests for detecting presence of disease. Statistic Med 2002;21: 52-853. 30. Lavalle G, Onori ME. Relationship between Serum 25- Hydroxyvitamin D and Thyroid Hormones during Pregnancy in the North of Rome. Int J Sci Res 2012;3:2319-7064. 31. Moon H-W, Chung H-J, Hur M, Yun Y-M. Vitamin D status and thyroid autoimmunity in Korean pregnant women. J Matern Fetal Neonatal Med 2015;28:2210-3. 32. Mohammed Nizar B, Battikhi Z, Battikhi B. Correlation of Serum 25- Hydroxyvitamin D and Thyroid Hormones in Pregnant Women in Amman-Jordan. J Microbiol Exp 2017;4:00099. 33. Musa IR, Rayis DA, Ahmed MA, Khamis AH, Nasr AM, Adam I. Thyroid Function and 25 (OH) Vitamin D Level among Sudanese Women in Early Pregnancy. Open Access Maced J Med Sci 2018 7;6:488-492. 34. Musa IR, Gasim GI, Khan S, Ibrahim IA, Abo-Alazm H, Adam I. No Association between 25 (OH) Vitamin D Level And Hypothyroidism among Females. Open Access Maced J Med Sci 2017;19:126-130. 35. Saler T, Keşkek S, Ahbab S, Cakir S, Ortoğlu G, Bankir M, et al. Frequency of Hashimoto's thyroiditis in women with vitamin D deficiency: A cross sectional study. Ame J Inter Med 2014;2:44-8. 36. Wang X, Zynat J, Guo Y, Osiman R, Tuhuti A, Zhao H, Abdunaimu M, Wang H, Jin X, Xing S. Low Serum Vitamin D Is Associated with Anti-Thyroid-Globulin Antibody in Female Individuals. Int J Endocrinol 2015;23:285290. 37. Boyuk B, Altay M, Atalay H, Guzel S, Celebi A, Ekizoglu I. No relationship between 25 OH vitamin D and autoimmunity in women patients with hypothyroidism. Acta Med Medit 2016;32:779-84. 38. Wang J, Lv S, Chen G, Gao C, He J, Zhong H, Xu Y. Meta-analysis of the association between vitamin D and autoimmune thyroid disease. Nutrients 2015 2485-98. 39. Hosseini MA, Salehi F, Yaghoubi Ma. Comparison of prevalence of vitamin D and Zinc deficiency in patients with hypothyroidism and healthy subjects. Mashhad University Med Sci J 2018;61:1188-96. 40. Mangaraj S, Choudhury AK, Swain BM, Sarangi PK, Mohanty BK, Baliarsinha AK. Evaluation of Vitamin D Status and its Impact on Thyroid Related Parameters in New Onset Graves' Disease- A Cross- sectional Observational Study. Indian J Endocrinol Metab 2019;23:35-39. 41. Chen X, He S-G, Shoenfeld Y, Zeng Y. Chapter 26 - Vitamin D, Pregnancy, and Autoimmunity: An Ongoing Mystery. In: Perricone C, Shoenfeld Y, editors. Mosaic of Autoimmunity: Academic Press 2019;259-67. 42. Kaur R, Yadav RS. Prevalence of Thyroid Autoimmunity and Vitamin D Insufficiency In Patients With Thyroid Disorders. Indian Journal of Applied Research 2019;9. 43. Hosny SS, Aboromia MM, Ibrahim NA, El Halim DKA. The relationship between vitamin D level and thyroid antibodies in primary hypothyroidism. The Egyptian J Inter Med 2019;31:164. 44. Bizzaro G, Shoenfeld Y.Vitamin D and autoimmune thyroid diseases: facts and unresolved questions. Immun Res 2015;61:46-52. 45. Zhao Y, Miao W, Li C, Yu X, Shan Z, Guan H, Teng W. Dynamic changes in serum 25-hydroxyvitamin D during pregnancy and lack of effect on thyroid parameters. PLoS One 2014 7;9:90161.

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Table 1: Comparison of the basic characteristic and calcium levels in case (with vitamin D deficiency) and control (without vitamin D deficiency) groups

Variable Groupsa (Mean± SD) P-valueb

Case control

Age of Mother (year) 31.1 ± 4.7 32.09 ± 4.3 0.08

Age of Marriage (year) 24 ± 4.2 23.5 ± 3.7 0.75

Gravid 2.2 ± 1.2 2.08 ± 1.1 0.26

BMI(Kg/m2) 25.2 ± 4.5 26.2 ± 4.2 0.48

Calcium 9.5 ± 5.3 9.6 ± 5.6 0.60 aData are presented as mean± SD SD: standard deviation bMann Whitney test BMI: Body Mass Index

Table 2: Comparison serum level of vitamin D3 and thyroid hormones in case and control groups

Variable Groupsa (Mean± SD) P-valueb

Case control Vitamin D (ng/dl) 16.7 ± 7.1 43.3 ± 14.1 0.001

TSH(mu/l) 2.2 ± 1.5 2.3 ± 2.05 0.51

FT3(ng/dl) 16.8 ± 42.9 20.07 ± 47.4 0.39

FT4 (ng/dl) 20.8 ± 32.5 14.4 ± 38.5 0.04 aData are presented as mean± SD SD: standard deviation bMann-Whitney test BMI: Body Mass Index

Table 3: Logistic regression analysis of effective factors on thyroid test function

Dependent variable Predictors variable βa Statistical Testb

t p T3

Age of Mother (years) 0.19 0.38 0.7

Gravid -0.02 -0.39 0.69

BMI (Kg/m2) - 0.01 -0.3 0.75

Vitamin D deficiency 0.01 -0.28 0.77

TSH

Age of Mother (years) -0.48 - 0.95 0.34

Gravid -0.06 -1.29 0.19

BMI (Kg/m2) 0.08 1.6 0.09

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Vitamin D deficiency -0.02 -0.54 0.58

T4

Age of Mother (years) -0.01 -0.19 0.84

Gravid 0.01 0.29 0.76

BMI (Kg/m2) - 0.01 -0.28 0.77

Vitamin D deficiency 0.12 2.49 0.01 βa: Beta coefficient. b Statistical Test: Liner regression

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